The Australian Research Council has funded a $400,000, 5-year study entitled ‘Cognitive neuropsychiatry: understanding delusional belief and delusional hallucination from a cognitive neuropsychological perspective’.

The study will be supervised by Dr. Robyn Langdon at the Macquarie Centre for Cognitive Science, and by Prof. Philip Ward at the Schizophrenia Research Unit, Liverpool Hospital.

Cognitive Neuroscience

Delusions and hallucinations are the archetypal signs of madness. Paranoid beliefs, grandiose religious confabulations, ‘hearing voices’, and seeing ‘little green men’ are such common symptoms of psychosis that they have been used to portray ‘insane’ characters in the arts throughout history. Sufferers of such symptoms often resist all appeals to commonsense and reason: they insist that their interpretation of events is true; that the ‘visions’ they see, or the ‘voices’ they hear, are real.

For well over a century, scientists have recognized that all the wonders of the mind are the province of the brain. Perception, emotion, planning and action, learning and memory, and all other aspects of cognition take place in the brain. The study of how the biological brain produces all the intangible qualities of mind is called cognitive neuroscience.

What is a delusion?

With the collaboration of Prof. Max Coltheart, Scientific Director of the Macquarie Centre for Cognitive Science, one aspect of the project is to recruit 60 schizophrenia subjects, and an equivalent number of controls, in a quest to better understand the causes of delusions.

The study will include an investigation into the ‘two-deficit’ theory which proposes that two distinct cognitive abnormalities must be present for a delusion to occur (Langdon & Coltheart, 2000). ‘Deficit 1′ involves the production of an abnormal thought, and ‘deficit 2′, the inability to review and reject that thought as implausible. The ‘two-deficit’ theory of delusion is the only existing cognitive neuropsychological model which attempts to explain all delusional conditions.

Using a variety of methods, this research aims to identify the specific functions of the brain that are disrupted in delusory thinking, thereby contributing to the design of more precise and effective anti-psychotic treatments.

Supported by an Ian Scott Fellowship grant from the Australian Rotary Health Research Fund, Nathan Clunas is in his second year investigating the brain function abnormalities that cause schizophrenia symptoms.

Event Related Potentials. When healthy and schizophrenia-affected research subjects hear the first beep through the earphones, their brains’ auditory systems respond strongly. If the beep is repeated immediately, the response is much weaker in both subjects. This is a normal ERP response. But if a longer interval is left before the following beep, healthy subjects will again record a weak response, but schizophrenia subjects may respond as strongly as they did to the first beep – indicating a faster ‘recovery cycle’ (recovery of the neurons’ excitability). This functional abnormality is thought to contribute to the inability to maintain attention and to attend selectively to relevant information which is symptomatic of schizophrenia. Measuring the brain’s response to auditory stimulation: Nathan Clunas fits earphones over the ‘Electrocap’ worn by a research subject.

Based at the Schizophrenia Research Unit, Liverpool Hospital, Nathan’s study has focussed on the brain’s auditory system because ‘hearing voices’ is one of the most common symptoms. As predicted in HeadLines March 2002, Nathan’s ERP studies have shown that auditory systems in schizophrenia-affected brains have a much faster ‘recovery cycle’ (recovery of the neurons’ excitability after firing). This abnormality may account for the inability to maintain attention, and other symptoms of the illness.

Nathan has received the rare honour of an invitation to give a platform presentation of his paper, “Altered Auditory Recovery Cycle Function in Schizophrenia: An ERP Study”, at the Annual Meeting of the Society for Neuroscience, to be held in New Orleans in November. Last year, 25,000 people attended this conference, the largest of its kind in the world.

The successful completion of the campaign to raise $200,000 for a schizophrenia research Beta Imager was celebrated with an opening ceremony at the University of Wollongong on 28 August.

Marilyn Mitchell, Patron of the ‘Gift of Hope’ brain donor program, spoke compellingly of her 20 years of struggle with schizophrenia, leaving the audience in no doubt about the new machine’s potential significance to the millions of people who suffer from the illness.

Prof. Philip Ward said the Beta Imager was central for the discovery of how the brain’s chemical systems malfunction in schizophrenia.

“This machine will enable SRI researchers to obtain results in hours which used to take months. Using this new knowledge, we may develop new treatments with fewer side-effects and better control of the debilitating symptoms,” said Prof. Ward.

The only one of its kind in the Southern Hemisphere, the Beta Imager is the result of a huge fundraising campaign championed by SRI’s Don McDonald, and strongly supported by South Coast unions, Wollongong Council, corporate leaders, Rotary Clubs, and news media.

University Contributes Research Fellowship

To match the South Coast community’s heroic fundraising efforts, the University of Wollongong has initiated a new 5-year post-doctorate Fellowship in schizophrenia research – the first such position to be funded by any NSW university.

The new Research Fellow, Dr. Chao Deng, will join Assoc. Prof. Xu-Feng Huang of the University’s Department of Biomedical Science, SRI Senior Research Officer Dr. Katerina Zavitsanou, and PhD student Kelly Newell in utilising the powerful research potential of the Beta Imager. Other Australian research groups will also access the machine.

One of the first research studies to benefit from the new Beta Imager will be Dr Katerina
Zavitsanou’s investigation into the effects of cannabis, a common trigger for first episode psychosis among teenagers.

The Beta Imager is already doing good work, analysing numbers of specific neuroreceptors in targeted areas of post-mortem brain tissue. The images A-D show by darker tinting that schizophrenia-affected brains contain abnormally large numbers of cannabinoid receptors (A-B) and abnormally small numbers of seratonin receptors (C-D).

While recent studies have reported that frequent cannabis use is associated with increased
risk for depression and anxiety among teenagers, the mystery remains why some young users develop mental illness, and others do not.

As reported previously, Dr Zavitsanou’s work has indicated that brain tissue from schizophrenia subjects contains abnormally large numbers of cannabinoid neuro-receptors (which play an important role in memory formation and goal-directed behaviour),suggesting that such brains
are particularly vulnerable to any disruptive effects of using cannabis.

Further research has now shown that such brains also contain abnormally small numbers of seratonin receptors – an important mood modulator.

The Beta Imager will accelerate progress in any further explorations of this promising line of research.

Investigation of the brain changes associated with schizophrenia and early and late onset long-term cannabis use.

The National Health and Medical Research Council (NHMRC) has awarded a project grant of $365,000 to SRI researchers for an investigation of the brain changes associated with schizophrenia and early and late onset long-term cannabis use.

Cannabis is used for its subjective effects that include euphoria, depersonalisation and somnolence. It is a controlled substance, yet one quarter of Australian adolescents
and seven percent of adults use cannabis regularly. Chronic use of cannibis can impair frontal brain functioning, affecting the capacities for attention, working memory and concentration.These
neurocognitive deficits bear striking similarities to those associated with the negative symptom cluster of schizophrenia,which is related to frontal brain dysfunction.

Images from SRI’s Brain Atlasing Initiative.

This study will be the first of it’s kind to apply sophisticated neuroimaging techniques to investigate how long-term adolescent cannabis use effects the structure and function of the
brain and to make comparative analyses with the brain changes associated with first episode schizophrenia.

It is thought that structural brain abnormalities that are consistent in localisation, if not in degree, will be detected in long-term cannabis using and first episode schizophrenia participants
and that there will be even more profound abnormalities in the first episode schizophrenia cannabis users.

The study will use the Tower of London (TOL) task to activate certain areas associated with executive functioning (for instance attention, memory, and strategic planning). Here, we expect lower intensity activation of the prefrontal cortex during TOL performance both in the cannabis and first episode schizophrenia groups and that the activation will be lowest of all for the cannabis using first episode schizophrenia group.

The methodology to be applied in this study offers a unique opportunity to enhance the understanding of the structural and functional markers of first episode schizophrenia
and cannabis use in the neural substrate.

The study will be conducted in Newcastle and Sydney and will be overseen by SRI-affiliates Prof. Vaughan Carr, Prof. Ulrich Schall, Dr Amanda Baker, Dr Martin Cohen, Pat Johnston
and Prof. Philip Ward.

SRI’s Brain Atlasing Initiative and collaborative link with Prof. Paul Thompson’s group
at the Laboratory of Neuro-Imaging, UCLA, was a vital ingredient in the successful award of funding to this research project.

How Rats and Mice Are Helping Schizophrenia Research The Sylvia and Charles Viertel Charitable Foundation awards $240K to SRI and the Queensland Centre for Schizophrenia Research to develop animal models of schizophrenia

The use of animal models in medical research has recently played a key role in the development of new understanding and treatments of such human diseases as diabetes, Alzheimers and MS, and is now also producing useful results for mental disorders.

How can rats and mice help schizophrenia research?
Mainly because any animal with a backbone uses the same neurotransmitter systems in the brain. By studying the interplay of excitatory and inhibitory substances in simpler nervous systems, we can learn more about the fundamental principles that govern the functions of all
brains.

An animal model does not have to reproduce all symptoms of a human disorder. Valuable research results can be obtained from an animal affected by a specific symptom of any illness. In
schizophrenia, for example, we know that some patients have difficulty sorting and prioritising sensory information. This deficit can lead to ‘negative’ symptoms, such as poor concentration and motivation.
Mice in a laboratory can be made to have similar problems by giving them drugs such as amphetamine or PCP. Once the symptoms have been produced in a mouse, researchers can measure its altered behaviour by monitoring performance in repeated tasks, and comparing it with that of untreated mice. Then researchers can study how dosing the mouse with other drugs, such as antipsychotics, can reduce the symptoms and normalise performance. In this way, finding therapies that work in the animal model may lead to more effective treatments for humans.

Because the DNA of mice is 98 per cent identical with human DNA, animal models can also be used to track down the genes responsible for the predisposition to mental illness. For example, researchers can create genetically altered mice (e.g. mice with a foreign gene added to their genetic makeup) and use them to examine the influence of specific genes on behavior. Recent advances in genetic engineering also allow investigators to activate or inactivate specific genes in specific regions of the brain. By switching genes on and off, and observing the chemical and behavioral effects caused, researchers can narrow down the list of suspect genes.

These are among the many research techniques to be applied in a collaborative research initiative funded by the Sylvia and Charles Viertel Charitable Foundation, and shared by
SRI and the Queensland Centre for Schizophrenia Research (QCSR).

Joining Forces and Sharing Resources

The new trans-state project will enable two of the major schizophrenia research groups in Australia to build a shared resource of skills, research instruments and animal models,
thereby creating a critical mass capable of significant breakthroughs to new knowledge.

The NSW-QLD collaboration will initially focus on developing two current lines of research. First, the vitamin D deficiency hypothesis presented by Prof. John McGrath of QCSR in 1999*. This theory suggested that a lack of sunlight during winter months pregnancies can lead to a vitamin D deficiency affecting the baby’s developing brain. Second, the current SRI research using mice with genetically reduced numbers of NMDA neuroreceptors. Earlier research has indicated that blocking these receptors in the brains of human and animal subjects produces schizophrenia-like
symptoms. Therefore investigating how the action of anti-psychotic drugs reduces symptoms in the NMDA depleted mice may provide new clues to how such drugs work, and to the genetic origins of schizophrenia
symptoms.

Big Federal Support for Major Research DiscoveryDistortions in sound processing a clue to schizophrenia risk

The National Health and Medical Research Council (NHMRC) has awarded a project grant of $360,000 to expand upon current investigations into an important discovery made in 1991 by members of the scientific group which initiated SRI.

Awarded to Dr Ulrich Schall and Professors Pat Michie, Philip Ward and Paul Thompson, the grant follows an initial NHMRC award of $250,000 made in 2001 to develop this line of research.

In 1991, a team including Professors Pat Michie, Stan Catts, Philip Ward, Sally Andrews, Neil McConaghy and Dr. Anne-Marie Shelley found that schizophrenia patients have a reduced brain response to deviant sounds in a repeating sequence of identical sounds.

In the original study, patients did a computer task involving coloured shapes while being presented via earphones with a repeating pattern of identical sounds, occasionally interrupted
by a different sound. In such tests, even though subjects ignore the noise on the earphones, the brain recognises the different sounds, and produces an electrical response known as mismatch negativity. This response can be recorded via Electrocap sensors placed on the
head.

Interestingly, further research by Prof. Michie indicated that first-degree relatives of schizophrenia patients produce similar reduced responses in mismatch negativity tests.

The importance of the original finding was that smaller responses in this auditory test could indicate serious deficits in brain function. For the brain to respond to a deviant sound, it must have a memory of past sounds, so a mismatch negativity test could be used as a measure of memory integrity, and of other high level functions.

1. Research subjects listen to repeated identical sounds through earphones while brain responses are monitored by
Electrocap sensors. Whenever the sequence of identical sounds is interrupted by a different sound, the brain registers a ‘mismatch negativity’ (MMN) response. Schizophrenia patients and their close relatives record a lower level of response (the black dotted line) than control subjects (the grey line).
2. To identify the brain areas involved in MMN, fMRI brain scans will be made while subjects listen to the sequence of sounds.
3. These fMRI images will then be digitally processed to identify any structural differences between schizophrenia subjects and controls in the brain areas identified.
4. Subjects will also provide blood and tissue samples for cDNA microarray analysis which will investigate any abnormalities in
the gene expression profiles of the MMN brain areas.

The new NHMRC funded project will use fMRI brain scans to examine patients who have recently developed schizophrenia; those who have suffered from the illness for longer periods of time,
and the close relatives of these patients. The specific brain regions that are active during auditory information processing will be identified, and linked to the individual brain areas identified via ERP. The new structural sMRI analysis tools used by the SRI Brain Atlasing
Initiative will then be applied to identify any differences in brain tissue structure in the areas targeted.

The fourth arm of the investigation, microarray analysis, is funded by SRI and supervised by Dr Paul Tooney. Blood samples and skin biopsies will be collected from research subjects, and microarrays will be used to compare the levels of expression in genes, and their correlations with the other results of the collaborative study.

The combined results from this research project have the potential to not only identify genes involved in causing schizophrenia, but also to provide a means whereby individual risk
of the illness may be measured.

SRI’s Brain Atlasing Initiative and collaborative link with Prof. Paul Thompson’s group at the Laboratory of Neuro Imaging, UCLA, was a vital ingredient in the successful award of
funding to this research project.